Endothelium and acute coronary syndromes

The vascular endothelium is a dynamic endocrine organ that regulates contractile, secretory, and mitogenic activities in the vessel wall and hemostatic processes within the vascular lumen. Risk factors for atherosclerosis such as cigarette smoking, hypertension, and increased serum lipid concentrations impair endothelial function and lead to the development of atherosclerotic vessels, which cause acute coronary syndromes. Atherosclerotic vessels progress from scattered foam cells to complex lesions with a lipid core and fibrous cap. Factors that weaken and cause the rupture of the fibrous cap will expose circulating blood products to the procoagulant materials in the lipid core. Thrombosis and subsequent remodeling of the unstable plaque may be catastrophic or clinically silent depending on the degree of vascular occlusion and availability of collateral blood flow. Evidence is presented that supports the view that endothelial dysfunction is an early marker of atherosclerosis and an important contributor to the atherogenic process.

The vascular endothelium is the inner lining of blood vessels and serves as an important autocrine/paracrine organ that regulates vascular wall contractile state and cellular composition (1)(2). Because of its strategic location between the circulation and the vascular wall, the endothelium interacts with both cellular and hormonal mediators from these two compartments. There is growing evidence that endothelial dysfunction, which is often defined as the decreased synthesis, release, and/or activity of endothelial-derived nitric oxide (NO),¹ is an important factor leading to atherosclerosis and acute coronary syndromes (3)(4). This realization, in part, is because the lack of NO in atherosclerotic vessels contributes to impaired vascular relaxation (5)(6), platelet aggregation (7), increased vascular smooth muscle proliferation (8), and enhanced leukocyte adhesion to the endothelium (9)(10). Indeed, vasoconstriction, platelet activation, and thrombosis caused by the rupture of atherosclerotic plaques are primary features of acute coronary syndromes (11)(12).

In addition to endothelial dysfunction, another important feature of atherosclerotic vessels is endothelial cell activation (13)(14). The activated endothelium expresses cell-surface adhesion molecules such as vascular cell adhesion molecule (VCAM)-1, intercellular adhesion molecule-1, and endothelial-leukocyte adhesion molecule (E-selectin), which facilitate the attachment of circulating leukocytes to the endothelium (15). Monocyte adhesion to the vessel wall and its subsequent differentiation into macrophages are crucial events leading to the development of macrophage-derived foam cells in atherosclerotic plaques (16)(17). Cytokines, oxidized low-density lipoproteins (ox-LDL), and infectious agents such as cytomegalovirus and Chlamydia pneumonia promote vascular oxidation and inflammation, which lead to endothelial cell activation (18)(19)(20)(21). Thus, endothelial dysfunction and activation caused by coronary risk factors and vascular inflammation are the basis for the development of atherosclerotic lesions and acute coronary syndromes (Fig. 1 ).

View larger version (18K): [in this window] [in a new window]   Figure 1. Factors that lead to endothelial dysfunction and activation. Endothelial dysfunction itself can also produce endothelial cell activation. ROS, reactive oxygen species; AGE, advanced glycation end products; and SMC, smooth muscle cell.

Endothelial Function

The endothelium produces vasoactive substances in response to environmental factors such as blood flow, oxygen tension, and receptor-mediated stimulants (Table 1 ) (22)(23)(24). Endothelial function is usually determined by vessel diameter, vascular contractility, or blood flow in response to endothelium-dependent agonists such as acetylcholine or bradykinin. Changes in vessel diameter are determined by angiography or ultrasonography, whereas alterations in blood flow or vascular resistance are determined by forearm or lower extremity strain-gauge plethysmography. Vascular contractility is measured by force transducers in an in vitro bioassay organ chamber.

Endothelium-dependent vascular relaxation is predominantly mediated by NO, and to lesser degrees, by prostacyclin and activators of ATP- and calcium-sensitive potassium channels (i.e., hyperpolarizing factor). Endothelium-derived vasoconstrictive substances include endothelin (ET)-1 and thromboxane A2. The balance between these opposing endothelium-derived vasoactive substances under nonpathological and pathological conditions ultimately determines the contractile and perhaps the mitogenic state of the underlying vascular smooth muscle.

Endothelium-derived NO or a closely-related molecule was initially described as endothelium-derived relaxing factor (EDRF) (25)(26)(27). The activity of endothelium-derived NO plays an important physiological role in the regulation of blood pressure and blood flow and has been widely used as a clinical marker of endothelial function. Endothelial dysfunction or the lack of EDRF is often associated with cardiovascular diseases such as hypertension, atherosclerosis, and congestive heart failure (28)(29)(30). The mechanism by which NO causes vasodilation is well known and occurs through the stimulation of soluble guanylyl cyclase activity in vascular smooth muscle. However, there is growing evidence that NO may exert other effects on the cardiovascular system independent of cyclic GMP (31)(32). As a result, the functional roles of NO in the cardiovascular system have expanded beyond those of a vasodilator.

NO is synthesized in many cell types from the conversion of L-arginine to L-citrulline (33). At least three distinct NO synthases (NOSs) have been identified and found to produce various amounts of NO under different conditions (Table 2 ) (34)(35)(36). For example, both the neuronal (Type I nNOS) and endothelial (Type III eNOS) isoforms are calcium-dependent and produce low concentrations of NO constitutively; whereas, sustained, high concentrations of NO are produced by macrophages or smooth muscle (Type II iNOS) only after induction by certain cytokines. Such unique differences in the regulation and localization of these NOSs may underlie their importance and contributions in the cardiovascular system.

Vessels affected by atherosclerosis develop endothelial dysfunction, as indicated by impaired vasomotor function because of loss of endothelium-derived NO activity (25)(37). It remains uncertain whether this aspect of endothelial dysfunction serves merely as a marker for atherosclerosis or is an important contributor to the atherogenic process. Growing evidence, however, indicates that NO exerts antiatherogenic and antiinflammatory actions. As previously mentioned, the loss of endothelium-derived NO activity contributes to impaired vascular relaxation (19)(37), enhanced platelet aggregation (7)(38), increased vascular smooth muscle proliferation (8), and greater endothelial-leukocyte interactions (9)(10)(39). Mutant mice lacking endothelial NOS have hypertension and develop greater proliferative and inflammatory vascular response to cuff injury (40)(41). Furthermore, inactivation of endothelium-derived NO by superoxide anion (O₂^-) limits the bioavailability of NO and leads to nitrate tolerance, vasoconstriction, and hypertension (42)(43).

In contrast, in vivo transfer of the endothelial NOS gene into balloon-injured rat carotid arteries decreases intimal smooth muscle cell proliferation (44). Enriching the diets of cholesterol-fed rabbits with L-arginine, the precursor of NO, improves endothelium-dependent relaxation, reduces leukocyte attachment to the endothelial surface, and limits the extent of atherosclerotic lesions (45)(46). Indeed, a single bolus treatment of a NO-generating compound, S-nitrosothiol, inhibits intimal smooth muscle proliferation in the balloon-injured rabbit carotid artery (47). Taken together, these studies suggest that endothelial function as defined by NO production and/or bioavailability may play an important role in suppressing the atherosclerotic process.

Endothelial dysfunction may also be attributed to abnormal or excessive release of vasoconstricting substances such as ET-1 (48). Indeed, circulating concentrations and tissue immunoreactivity of ET-1 are increased in patients with advanced atherosclerosis and acute coronary syndromes (49)(50). Whereas NO is vasodilatory and antiproliferative in its effects on the underlying vascular smooth muscle, ET-1 is vasoconstrictive and mitogenic. Exposure to cardiovascular risk factors such as oxidized LDL enhances the production and release of ET-1 (51). Increased ET-1 concentrations in combination with platelet-derived growth factors promote vascular smooth muscle proliferation in the neointima of atherosclerotic lesions (52). Although definitive proof that ET-1 is a primary inducer of atherosclerosis is still elusive, it is highly likely that ET-1 is at least an important contributor to the atherogenic process.

Atherogenic Risk Factors and Endothelial Function

Numerous studies demonstrate that endothelial dysfunction is one of the earliest manifestations of atherosclerosis even in the absence of angiographic evidence of disease (53)(54)(55). Conversely, improved endothelial function is one of the earliest clinical markers of atherogenic risk factor modification. There is a strong association between atherogenic risk factors and endothelial dysfunction (Table 3 ). For example, LDL, especially oxidized LDL, is a potent inhibitor of endothelial function (56). The mechanisms by which LDL inhibits endothelium-derived NO activity include down-regulation of endothelial NOS expression (57), decreased receptor-mediated NO release (58), and NO inactivation via increases in superoxide anion production (59). Indeed, endothelial dysfunction is a hallmark of hypercholesterolemia and rapidly improves with cholesterol reduction (60)(61).

Large clinical studies has shown beneficial effects of cholesterol reduction on cardiovascular mortality even in patients with average cholesterol concentrations (62)(63)(64). Furthermore, endothelial dysfunction correlates with male gender, increasing age, hypertension, and diabetes mellitus (65)(66)(67). The association between atherogenic risk factors and endothelial dysfunction is corroborated by studies demonstrating that endothelial function improves after risk factor modifications such as cholesterol reduction, smoking cessation, and estrogen replacement therapy (60)(61)(68)(69).

Morphologic and Functional Stages of Atherosclerosis

The current model of atherogenesis is based on the "response to injury" hypothesis (70). The basic tenet is that injury to the endothelium by local disturbances of blood flow at certain branch points of the arterial tree coupled with systemic factors such as hypercholesterolemia, hyperglycemia, cigarette smoking, and microbial infections initiates a cascade of events that ultimately leads to the development of the atherosclerotic lesion (Fig. 2 ) (11)(12). During the early phase of atherosclerosis, there is absence of gross morphologic changes within the vessel wall, except for isolated macrophages containing minimal oxidized lipid droplets. However, in this early Type I lesion, some activation of endothelial cells and impairment of endothelium-dependent vasodilation can be demonstrated in the absence of gross endothelial cell damage.

View larger version (28K): [in this window] [in a new window]   Figure 2. Evolution of the atherosclerotic lesion. The various stages of atherosclerosis are divided into two phases: the early lipid accumulation phase and the late intimal smooth muscle proliferation and thrombosis phase. Lesions in stages I–IV (Types I–IV) do not cause appreciable stenoses. Lesions in stages V and particularly VI (Types V and VI) can be quite obstructive. Cycling between stages V and VI may represent the natural progression or growth of the atherosclerotic lesion.

Endothelial dysfunction and endothelial cell activation lead to increased platelet aggregation and enhanced leukocyte adhesiveness to the vessel wall (71)(72). In response to lipids, especially in the oxidized form (i.e., oxidized LDL), vascular endothelial and smooth muscle cells secrete monocyte chemotactic protein-1 and macrophage colony-stimulating factor (M-CSF or CSF-1), which promote monocyte chemotaxis, adhesion, and differentiation into macrophages (16)(17). Macrophages in the vessel wall avidly accumulate oxidized lipids. Lipid accumulation in macrophage-derived foam cells and vascular smooth muscle cells form the fatty streak that is characteristic of Type II lesions. The endothelium in Type II lesions is morphologically intact although its function is impaired.

In Type III or intermediate lesions, lipid accumulation begins to overwhelm the uptake by macrophage-derived foam cells, and small extracellular lipid pools appear within the vessel wall. In addition, macrophage-derived cytokines, platelet-derived growth factors such as platelet-derived growth factor and transforming growth factor-ß1, and lipid pools stimulate the proliferation and migration of adjacent smooth muscle cells, forming the intimal layer of atherosclerotic lesions. Although Type III lesions possess lipid-laden macrophages and exhibit intimal smooth muscle proliferation, these lesions rarely encroach substantially on the vascular lumen because of compensatory dilatation of the vessel wall.

When the small extracellular lipid pools in the intima of a Type III lesion coalesce into a more organized dense lipid collection or lipid core, the lesion is sufficiently advanced to be classified as a Type IV lesion, or atheroma. Between the lipid core and endothelium of the atheroma is the proteoglycan-rich intimal layer containing mostly smooth muscle cells and macrophages and, to a lesser extent, T lymphocytes and mast cells. These inflammatory cells are concentrated particularly in the lateral or "shoulder" region of the atheroma. Fibrosis is not a predominant feature of Type IV lesions, and therefore, the atheroma is structurally weak and may be susceptible to fissuring from mechanical or tensile forces. Again, the endothelium covering the atheroma is functionally impaired with respect to NO release, allowing continued monocyte adhesion and influx into the vessel wall.

If the atheroma does not fissure, the smooth muscle cells within the intima will lay down collagen, forming a dense fibrous cap characteristic of a Type V lesion or fibroatheroma. Often the proliferation of intimal smooth muscle cells and the formation of connective fibrous tissue exceed the thickness of the underlying lipid core and cause substantial diminution of the vascular lumen. These fibrous plaques may sometimes become calcified, where mineralization may replace the entire lipid core. The stability of Type V lesions depends on the strength and thickness of the fibrous cap relative to the size of the lipid core. If the fibroatheroma is weakened by increased tensile forces or by enzymatic degradation of the fibrous cap by metalloproteinases such as collagenase, gelatinase, and elastase, then the plaque may rupture and expose highly thrombogenic material from its lipid core. This results in the complicated Type VI lesions, where hemorrhage-hematoma and thrombus formation may eventually occlude the vascular lumen, giving rise to acute coronary syndromes.

The morbidity and mortality associated with atherosclerosis are predominantly because of the rupture of Types IV and V lesions, with ensuing hematoma and thrombus formation, which occludes the vessel lumen (73). In most cases, the vessel repairs itself without major sequelae to the individual, although the atherosclerotic lesion develops surface defects, hematoma, and ulcerations, which can further compromise blood flow. In most myocardial infarctions, plaque rupture with thrombus formation is observed in the culprit vessel. It should be noted again that Types I–IV lesions are usually clinically silent because the lesions do not encroach substantially on the vessel lumen. Types V and VI lesions, however, are usually obstructive and are commonly the pathological basis of acute coronary syndromes (11)(12)(71)(73).

Inflammation and Atherosclerosis

Accumulating evidence indicates that atherosclerosis is an immunologic process involving a network of vascular wall cells, mononuclear cells, T lymphocytes, cytokines, and growth factors (18). Macrophages, T lymphocytes, and vascular wall cells, particularly smooth muscle cells, elaborate cytokines and growth factors that regulate the cellular and matrix composition of the vascular wall. For example, cytokines stimulate collagen synthesis in smooth muscle cells and promote endothelial and vascular smooth muscle cell activation through the induction of cellular adhesion molecules. Chemokines and growth factors such as monocyte chemoattractant protein-1 and M-CSF promote monocyte chemotaxis and attachment to the endothelium and support their survival and differentiation into macrophage-derived foam cells. Thus, it appears likely that any effective strategy designed to counter the atherogenic process will have to take into account modulation of the immune system with the vessel wall.

The presence of cytokines and inflammatory mediators within the vascular wall has invoked speculation that atherogenesis may be the result of chronic infectious processes similar to that of duodenal ulcers caused by Helicobacter pylori (74). Indeed, serum markers of chronic inflammation, such as C-reactive protein and serum amyloid A protein, are increased in patients with atherosclerotic heart disease (75)(76). Several infectious agents have been implicated in the atherogenic process including the herpes viruses, cytomegalovirus, and C. pneumoniae. For example, the immunohistochemical localization and antibody titer for C. pneumoniae correlate with increased incidence of coronary heart disease (77)(78).

With most of these infectious agents, however, rarely is the causative organism ever recovered from tissue specimen. Thus, controversy exists regarding whether microbial infections cause atherosclerosis because one of Koch's postulates has not been demonstrated. However, Koch's original postulates may be more applicable to acute rather than chronic infections. Because atherosclerotic lesions take three to four decades to develop, the causative organism that may have initiated the inflammatory process may no longer be present. Herein lies the "hit and run" hypothesis of atherosclerosis, where infectious agents may initially cause endothelial dysfunction and vascular inflammation without being present in the later stages of plaque development.

Oxidant Stress and Atherosclerosis

Some recent clinical trials have demonstrated beneficial effects of antioxidant therapy in individuals with atherosclerotic heart disease (79). These findings suggest that the development of atherosclerosis and acute coronary syndromes may be mediated, in part, by an oxidative process (Fig. 3 ). Oxidant stress leads to LDL oxidation, which inhibits EDRF release more than native or unoxidized LDL. Furthermore, LDL that is oxidized is more readily taken up by macrophages through the scavenger receptor than native LDL. The major sources of oxidants and reactive oxygen species in the atherosclerotic vessel are the macrophages and smooth muscle cells. Indeed, hypercholesterolemia stimulates the generation of superoxide anions from vascular smooth muscle cells, which can further oxidize LDL (59). In addition, superoxide anions may cause endothelial dysfunction by scavenging endothelium-derived NO (42). Recent studies have shown that antioxidants such as probucol, vitamin C, and vitamin E improve endothelial function, attenuate endothelial cell activation, and reduce cardiovascular events in individuals with atherosclerosis (79). However, the use of antioxidant therapy in acute coronary syndromes is still controversial because other studies using antioxidants do not show definite beneficial effects on endothelial function and cardiovascular morbidity (80).

View larger version (13K): [in this window] [in a new window]   Figure 3. Redox balance in the vascular wall. Oxidants, especially superoxide anion (O2-·) and its dismutated product hydrogen peroxide (H2O2) produced by vascular smooth muscle cells and macrophages oxidize LDL and activate oxidant-sensitive transcription factors such as NF-B, leading to the transcriptional induction of pro-inflammatory genes. Hydroxyl radical (·OH) is generated by catalysis of H2O2 in the presence of transitional metals, whereas peroxynitrite (ONOO-) is formed by the interaction of (O2-·) and nitric oxide (·NO). The cellular antioxidant or antiinflammatory mechanisms include ·NO, glutathione (GSH), superoxide dismutase (SOD), and catalase. Note that ·NO can participate on both sides, depending on the environmental milieu.

One mechanism by which oxidant stress may contribute to the atherogenic process is via the induction of pro-inflammatory mediators. For example, the activation of pro-inflammatory transcription factors such as nuclear factor-kappa B (NF-B), activator protein (AP)-1, and early growth response factor (egr)-1 occur through oxidant-sensitive mechanisms involving hydrogen peroxide (H₂O₂) (81)(82)(83). Because cellular adhesion molecules such as VCAM-1, intercellular adhesion molecule-1, and E-selectin and many cytokines and growth factors such as M-CSF contain functional DNA-binding sequences for NF-B, AP-1, and egr-1, their expression is induced by the activation of these transcription factors (84). Indeed, the NF-B activation is found in intimal smooth muscle cells of atherosclerotic lesions (85).

Interestingly, NF-B activation is inhibited by antioxidants and antiinflammatory agents such as salicylates and glucocorticoids (86)(87)(88). These findings suggest that atherosclerosis is an inflammatory process initiated and propagated by oxidative stress. Thus, antioxidants may protect against the development of atherosclerosis by inhibiting the activation of pro-inflammatory transcription factors that are required for the induction of cellular adhesion molecules, cytokines, and growth factors in the vessel wall.

Mechanisms of Plaque Rupture

As previously mentioned, Types IV and V lesions are particularly susceptible to disruption by mechanical forces. The rupture of atherosclerotic plaques and exposure of procoagulant materials (i.e., tissue factor) within the lipid core cause acute thrombus formation. Indeed, findings from thrombolytic trials demonstrate that the majority of acute myocardial infarctions are precipitated by plaque rupture with ensuing thrombus formation and luminal obstruction (89). Angiographic studies, however, performed after successful thrombolytic therapy revealed that, in most cases, the culprit lesion producing the occluding thrombus did not exhibit high-grade stenosis (90)(91)(92). The premise that plaque stability and not luminal stenosis is of primary importance is supported by numerous clinical trials with lipid-lowering agents, showing improved cardiac morbidity and mortality in the absence of substantial changes in angiographic stenosis (93). Thus, plaque stability rather than its abluminal encroachment determines the propensity of the lesion to develop into an acute coronary syndrome.

Many Types IV and VI lesions, however, do not rupture, and of the plaques that do rupture, the majority probably occur without symptoms. Asymptomatic plaque rupture may occur with nonoccluding thrombi or in vessels with sufficient collateral circulation to maintain perfusion. Indeed, plaque rupture is observed at autopsy in 9% of individuals with noncardiac deaths and 22% of individuals with diabetes and hypertension (94). Thus, subclinical plaque rupture with subsequent healing and reorganization may actually represent a natural progression of many atherosclerotic lesions.

The fibrous cap of the atherosclerotic plaque separates the luminal clotting cascade from its procoagulant lipid core. Thus, factors that enhance the tensile strength of the fibrous cap relative to the its lipid core will ultimately make the plaque less vulnerable to rupture (Table 4 ). For example, less mechanical force is required to disrupt the plaque if the fibrous cap is relatively thin and devoid of intimal smooth muscle cells and collagen (i.e., thin fibrous cap). Recent studies demonstrate the presence of T lymphocytes and the expression of major histocompatibility class II in intimal smooth muscle cells within the fibrous cap (95)(96). The expression of major histocompatibility class II antigens indicates the presence of the lymphokine, interferon-, which inhibits collagen synthesis, and which, in combination with other cytokines, induces vascular smooth muscle cell death by apoptosis (97). Both of these effects of interferon- weaken the fibrous cap and make the plaque much more vulnerable to rupture.

Another determinant of plaque stability is the size of the lipid core relative to the thickness of its fibrous cap. Less tensile force is required to disrupt the plaque if a large lipid core containing liquified cholesterol ester is surrounded by a very thin, acellular, collagen-deficient fibrous cap. By mathematical modeling, the greatest mechanical force on the atherosclerotic lesion is exerted toward the shoulder region of the plaque, where the point of rupture frequently occurs (98). Ironically, the greater the luminal stenosis, the lesser is the circumferential force exerted on the atherosclerotic lesion. This may explain why lesions with the greatest lumenal stenoses, which cause chronic ischemia, are usually the more stable lesions with respect to plaque rupture. Conversely, the nonobstructive atheroma or Type IV lesion, which has a nonfibrous, thin cap and does not cause lumenal obstruction, is often more susceptible to rupture compared with a more advanced, highly stenotic, fibrocalcific lesion.

The fibrous cap can be substantially weakened by matrix degrading enzymes known as matrix metalloproteinases (MMPs) (99)(100). The MMPs are a family of extracellular enzymes that include interstitial collagenases and gelatinases. Exposure of macrophages and smooth muscle cells to certain cytokines such as interleukin-1 and tumor necrosis factor- induce the expression and activity of interstitial collagenases within the fibrous cap (101)(102). Because the strength of the fibrous cap is due to matrix proteins such as proteoglycans and collagen, the induction and activation of MMPs result in the thinning and weakening of the fibrous cap and would therefore make the plaque more susceptible to mechanical disruption.

Role of Endothelium in Atherosclerosis and Plaque Rupture

In addition to increasing blood flow through local vasodilation, the endothelium prevents platelet aggregation (7), smooth muscle cell proliferation (8), and monocyte adhesion (9)(10). As previously mentioned, platelet aggregation leads to the release of mitogens such as platelet-derived growth factor and transforming growth factor-ß1 and thrombosis of the vascular lumen. The growth factors released by platelets stimulate the vascular smooth muscle cells to proliferate, thus generating the intima of atherosclerotic lesions.

Endothelium-derived NO inhibits the expression of cellular adhesion molecules on the endothelial surface and thereby prevents leukocyte attachment to the vessel wall (31)(103). Furthermore, inhibition of endogenous endothelial NO production by N^G-monomethyl-L-arginine mildly induces VCAM-1 expression in cultured saphenous vein endothelial cells (Fig. 3 ) (104). Similarly, higher concentrations of NO are required to inhibit cytokine-induced endothelial adhesion molecule expression (31)(103). The mechanism by which NO inhibits the expression of cellular adhesion molecule is via inhibiting the activation of the pro-inflammatory transcription factor, NF-B (31)(103)(104)(105).

Because many cytokines, growth factors, and adhesion molecules depend on NF-B for their transcriptional induction (84), the regulation of NF-B by NO is an important mechanism by which the endothelium and other NO-producing cells can modulate the expression of pro-inflammmatory mediators during atherogenesis. The mechanism by which NO inhibits NF-B occurs, in part, via the up-regulation of the NF-B inhibitor, IB- (104)(105). Decreased NO production in endothelial dysfunction, therefore, would foster the activation of endothelial cells and the production of many cellular adhesion molecules and pro-inflammatory cytokines during atherogenesis (Fig. 4 ).

View larger version (18K): [in this window] [in a new window]   Figure 4. Endothelial dysfunction can lead to endothelial cell activation. Inactivation of or decreased production of NO allows many factors, such as integrins and oxidases, to activate the pro-inflammatory transcription factor, NF-B. Unhindered activation of NF-B leads to the expression of cellular adhesion molecules such as VCAM-1.

In addition, monocyte adhesion to the activated and dysfunctional endothelium allows the formation of macrophage-derived foam cells, which subsequently produce MMPs that degrade and weaken the fibrous cap and make the lesion more susceptible to plaque rupture. Thus, the loss of endothelial function in atherosclerotic lesions initiates a cascade of events that permit atherogenesis to proceed unchecked, ultimately culminating in lesions that are more likely to result in acute coronary syndromes.

Future Directions

Recent insights from vascular biology concerning the developmental stages of atherosclerosis have shed light on the importance of the endothelium as a modulator of vascular reactivity, atherogenesis, and plaque stability. Because endothelial dysfunction is an early marker of atherosclerosis and is precipitated by atherosclerotic risk factors, strategies designed to prevent acute coronary syndromes should focus on preserving endothelial function through risk factor modification. Lowering serum cholesterol concentrations would have the added benefits of increasing plaque stability by decreasing and solidifying the lipid core without necessarily affecting lumenal stenosis. In addition, any future strategies to combat acute coronary syndromes should target therapeutic modalities that improve endothelial function and strengthen the fibrous cap of atherosclerotic lesions.

Acknowledgments

This work is supported in part by grants from the National Institutes of Health (HL-52233) and the American Heart Association (Established Investigigator Award).

Footnotes

Cardiovascular Division, Department of Medicine, 221 Longwood Avenue, LMRC-316, Boston, MA 02115. Fax 617-264–6336; e-mail jliao{at}bustoff.bwh.harvard.edu.

¹ Nonstandard abbreviations: NO, nitric oxide; VCAM, vascular cell adhesion molecule; ET, endothelin; EDRF, endothelium-derived relaxing factor;NOS, nitric oxide synthase; M-CSF, macrophage-colony stimulating factor; NF-B, nuclear factor-kappa B; AP, activator protein; egr, early growth response factor; and MMP, matrix metalloproteinase.

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